Acute liver failure: CNS effects

Neurological manifestations of both acute and chronic liver disease include hepatic encephalopathy, cerebral edema and seizures. Often, more than one of these is present as their pathophysiology is interrelated.

Hepatic encephalopathy has a variable clinical presentation but is often characterized by altered mental status in conjunction with other neurological signs including asterixis, hyperreflexia and inverted plantar reflex. It can be classified from grade 1 (anxiety, decreased attention span) to grade 4 (deep coma), with a higher grade associated with a worse prognosis. Circulating levels of ammonia and other neurotoxins are believed to be precipitating factors. Other factors include disruption of the blood brain barrier, increased inhibitory neurotransmission (flumazenil has been shown to reverse some symptoms), and altered cerebral energy metabolism. The degree of encephalopathy seems to correlate with the degree of shunting of portal blood into systemic circulation. Treatment includes oral lactulose and neomycin, which serve to reduce intestinal ammonia absorption.

In the brain, ammonia is metabolized by astrocytes. In order to detoxify ammonia, these cells produce glutamate which is metabolized to glutamine. High levels of glutamine act as an osmotic agent causing water to move into the astrocytes, leading to swelling and cerebral edema. Elevated ICP secondary to cerebral edema accounts for approximately 25% of all deaths in acute liver failure. Cerebral edema most often occurs in patients with advance hepatic encephalopathy, and those with rapid onset (e.g. acetaminophen poisoning) are at especially high risk.

Seizures have also been associated with patients in acute liver failure. Persistent seizure activity can cause cerebral hypoxia leading to worsening of cerebral edema and encephalopathy. Additionally, a postictal state should be on your differential for AMS when working up a patient with potential hepatic encephalopathy, as well as other causes that may be present in a patient with liver disease such as hypoglycemia or intracranial bleeding.